The main objective of the grant proposal will be to determine the mechanisms that underlie homosynaptic long-term depression (LTD) in Aplysia californica sensorimotor synapses in culture. LTD is a form of synaptic plasticity that is thought to represent a cellular correlate for mammalian learning and memory. Although it is believed to underlie learning, LTD remains inconclusive regarding a behavioral role in learning. Our laboratory believes that LTD can underlie long-term habituation a simple learning behavior that has been well defined and studied in Aplysia. Thus, determining mechanisms of LTD in culture will lend insight into the behavior of the animal. Previous work from our lab has shown that LTD of Aplysia sensorimotor synapses requires a postsynaptic rise in intracellular calcium. Experiments will test if the rise in calcium is mediated by activation of postsynaptic N-methyl-D-aspartate (NMDA) receptors. Experiments will also test for other possible targets such as metabotropic glutamate receptors, L-Type calcium channels or intracellular calcium store activation. Furthermore, the proposed project will test for the role of protein phosphatase activation and the role of AMPA receptor endocytosis in the induction of LTD at Aplysia sensorimotor synapses in culture. Ultimately, the results from the project will increase our knowledge on the cellular correlates of synaptic plasticity in the Aplysia central nervous system while contributing to the general understanding of human related diseases such as Alzheimers and other related human-learning deficits. [unreadable] [unreadable]